MENDELIAN INHERITANCE2002

• Genotype• Phenotype• Locus• Allele• Homozygote/ Heterozygote• Compound heterozygote• Proband

A. ADB. ARC. XLRD. XLDE. Not genetic

Mozart’s Piano Concerto in A-major is Köchel number

• A K365• B K450• C K482• D K488• E K491

Clinical vignette

• S G: 20 yo college student– Spontaneous rupture of the common iliac artery– Friable tissues, extensive bleeding– Past history:

• Easy bruising• Lax joints (fingers, elbows, left shoulder)

• D G: 53 yo mother of SG– Spontaneous perforation of the sigmoid colon– Past history

• Easy bruising• No joint laxity• Two normal pregnancies

Laboratory analysis

• Skin fibroblasts: abnormal type III collagen

• COL3A1 DNA analysis: Gly25Val

• Diagnosis: Ehlers-Danlos Syndrome,

Type IV

Pedigree symbols

Autosomal dominant inheritance

• Vertical

• Males and females affected

• Males and females transmit

• Each affected has one affected parent…

NF1

Café-au-lait

Neurofibroma

Lisch Nodules

Neurofibromatosis 1variable expressivity

• Café-au-lait spots

• Axillary freckling

• Lisch nodules

• Cutaneous neurofibromas

• Plexiform neurofibromas

• Scoliosis

• CNS tumors

Marfan syndrome

Marfan ectopia lentis

Marfan life expectancy

Marfan Syndrome variable

expressivity

Incomplete penetrance

AD Erythermalgia

Achondroplasia

What is the risk that this couple’s child will have achondroplasia ?

• A ¼

• B ½

• C ¾

• D 1

• E 0

Achondroplasia mutations in FGFR3

Allelic Heterogeneity

COL3A1 (EDS IV)

Autosomal Recessive

Autosomal Recessive

• Horizontal

• Males and females affected

• Parents of affected are normal

Autosomal recessive

A. ADB. ARC. XLRD. XLDE. Not genetic

Locus Heterogeneity

IV-1,2,3,4,5,6 are all double heterozygotes

congenital deafness

X-linked recessive

X-linked recessive inheritance

• “Diagonal”

• Males affected…

• Transmitted by carrier females

• NO male-to-male transmission

• Daughters of affected males are obligate carriers

X-linked recessive

inheritance

X-linked dominant

X-linked NOT sex-linked

Mitochondrial inheritance

• Mitochondrial DNA– 2 to 100 mitochondria/cell– 5 to 10 chromosomes/mitochondrium– 16.5 kb mt DNA– 37 genes

• Mitochondrial inheritance– Maternal– Heteroplasmy

MERRF

MERRF Pedigree

Heteroplasmy

Myotonic Muscular Dystrophy

• Most common inherited muscular dystrophy of adults

• Muscle wasting—face, neck, distal muscles• Myotonia• Cardiac and smooth muscle affected• Cataracts• Immunoglobulin abnormalities• Insulin resistance• Occ. Mild MR

Autosomal dominant

ANTICIPATION

DENIAL AIN’T JUST A RIVER IN EGYPT

-Rap song

The absence of evidence is NOT equivalent to evidence of absence

Triplet (CTG) Repeats

Repeat Expansion

Triplet Repeat Diseases

Pathogenesis of Myotonic Dystrophy

• Loss of Function– Haploinsufficiency of DMPK– Cis-chromatin effects

Cis-chromatin effects

Pathogenesis of Myotonic Dystrophy

• Loss of Function– Haploinsufficiency of DMPK– Cis-chromatin effects

• Gain of Function

Gain of Function

Ypsilanti

Demetrius Ypsilanti

Alexander Ypsilanti